MicroRNAs (miRs) have been implicated in a number of biological processes including regulation and maintenance of cardiac function (Van Rooij et al., “MicroRNAs: Powerful New Regulators of Heart Disease and Proactive Therapeutic Targets,” J. Clin. Invest. 117(9):2369-2376 (2007); Chien K R, “Molecular Medicine: MicroRNAs and the Tell-tale Heart,” Nature 447:389-390 (2007)). Therefore, miRs represent a relatively new class of therapeutic targets for conditions such as cardiac hypertrophy, myocardial infarction, heart failure, vascular damage, and pathologic cardiac fibrosis, among others. miRs are small, non-protein coding RNAs of about, 18 to about 25 nucleotides in length, and act as repressors of target mRNAs by promoting their degradation, when their sequences are perfectly complementary, or by inhibiting translation, when their sequences contain mismatches. The mechanism involves incorporation of the mature miRNA strand into the RNA-induced silencing complex (RISC), where it associates with its target RNAs by base-pair complementarity.
miRNA function may be targeted therapeutically by antisense polynucleotides or by polynucleotides that mimic miRNA function (“miRNA mimetic”). However, targeting miRNAs therapeutically with oligonucleotide-based agents poses several challenges, including RNA-binding affinity and specificity, efficiency of cellular uptake, and nuclease resistance. For example, when polynucleotides are introduced into intact cells they are attacked and degraded by nucleases leading to a loss of activity. While polynucleotide analogues have been prepared in an attempt to avoid their degradation, e.g., by means of 2′ substitutions (Sproat et al, Nucleic Acids Research 17:3373-3386 (1989)), the modifications often affect the polynucleotide's potency for its intended biological action. Such reduced potency, in each case, may be due to an inability of the modified polynucleotide to form a stable duplex with the target RNA and/or a loss of interaction with the cellular machinery. Other modifications include the use of locked nucleic acid, which has the potential to improve RNA-binding affinity (Veedu et al., “Locked Nucleic Acid as a Novel Class of Therapeutic Agent,” RNA Biology 6:3, 321-323 (2009)).
Oligonucleotide chemistry patterns or motifs for miRNA inhibitors have the potential to improve the delivery, stability, potency, specificity, and/or toxicity profile of the inhibitors, and as such are needed for effectively targeting miRNA function in a therapeutic context.